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Using Clinical Studies and Human-Based Models to Understand Vaccine Mechanisms Impacting Efficacy and Safety
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Topic Description
Post Date: June 3, 2026
Expiration Date: June 3, 2028
Vaccines are important public health interventions to reduce infectious disease incidence, severity and mortality. Understanding the biological mechanisms underlying vaccine efficacy, safety, non-target effects, and susceptibility to adverse events remains a central challenge. Traditional animal models are limited in their ability to capture human-specific pathways, susceptibility factors, long-term health effects, and immunological and developmental context. In addition, existing post-market surveillance systems face significant limitations in mechanistic understanding, as they generally capture disease outcomes without exploring biomarkers that may illuminate mechanistic pathways.
Both experimental approaches using human-based systems and observational studies in human participants can be used to explore the mechanistic pathways between vaccines and beneficial and adverse outcomes across the general population or specific subgroups.
Recent advances in New Approach Methodologies (NAMs), including human cell-based systems, organoids, microphysiological systems, biomarkers, and computational models, offer unprecedented opportunities to generate subpopulation-specific safety profiles and mechanistic data. These approaches enable direct interrogation of immune activation pathways, neuroimmune interactions, and maternal-fetal biology, as well as identification of susceptibility factors (e.g., genetic background, sex, developmental stage). Importantly, NAMs are well-suited to evaluate biological plausibility, dose-response relationships, and mechanistic coherence across systems, and can also be integrated with clinical and epidemiological data to understand patient- and population-level outcomes.
Despite these advances, NAMs have not been systematically applied to study how vaccine products, adjuvants or other component exposures and schedules may influence immune responses, neurodevelopmental processes, or affect other organ systems (non-target effects). Additionally, NAMs have not been applied to identify factors that may inform longer-term health trajectories. Integrating NAMs into a coordinated research framework is essential to move beyond descriptive associations toward causal, mechanistic understanding. Finally, biomarkers are critical tools for linking mechanistic insights from NAMs to clinical and population-level outcomes.
NIH seeks to encourage investigator-initiated research in the following areas:
• Validation, reproducibility, and regulatory alignment
• Elucidating immune activation pathways and reactogenicity mechanisms
• Modeling neuroimmune and neurodevelopmental mechanisms
• Characterizing maternal-fetal and early-life interfaces
• Evaluating cumulative and schedule-related effects
• Identifying susceptible subgroups and response modifiers
It aligns with:
- New Approach Methodologies (NAMs) : The expanded use of NAMs can enable earlier, more predictive insights into chronic disease mechanisms using human-relevant models such as organoids, computational simulations, and real-world data integration. This improves prevention, diagnosis, and personalized treatment strategies while reducing reliance on animal studies that often fail to replicate complex human conditions. The Environmental Protection Agency (EPA), Food and Drug Administration (FDA), and NIH have all committed to using NAMs moving forward, when appropriate.
- Vaccine Injury : HHS, in collaboration with NIH, will investigate vaccine injuries with improved data collection and analysis, including through a new vaccine injury research program at the NIH Clinical Center that may expand to centers around the country.
Participating ICOs
NIAID-relevant research utilizing clinical studies, human data, and human-based models to assess vaccine safety and efficacy across infectious and immune-mediated diseases includes:
- Elucidating mechanisms of vaccine-induced protection, durability, and correlates of immunity, including innate and adaptive responses.
- Distinguishing protective from atypical or exaggerated responses associated with adverse outcomes and reactogenicity.
- Characterizing factors that influence immune development and vaccine responses from fetal development through the lifespan.
- Modeling vaccine responses across schedules, populations, and susceptibility factors to inform safety and effectiveness.
- Identifying biomarkers and correlates of protection linked to factors including genetics, sex, and immune history.
- Developing and applying NAMs and other advanced models to study immune responses to vaccination, including repeated immune stimulation, tolerance, and durability.
The National Institute of Environmental Health Sciences (NIEHS) is interested only in applications that focus on the interaction between this topic and environmental exposures with relevance to human health outcomes. Environmental exposures of interest include, but are not limited to: air pollutants, pesticides, industrial by-products, trace elements (e.g., metals and metalloids), nanomaterials and microplastics, endocrine disrupting chemicals, persistent organic pollutants, emerging compounds and contaminants of concern, environmental radiation, and environmental exposures resulting from extreme weather events or disasters.
The NIEHS Worker Training Program and the Superfund Research Program are not participating in this topic.
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